Project Summary/Abstract Complex carbohydrates play important roles in a variety of biological functions and disease processes; however, their structural complexity and limited availability in homogeneous forms represent a major roadblock that hampers study of their important functions in numerous biological processes. While synthetic approaches that assemble nucleic acids and proteins have been well-established, the robust tools and technologies for complex-carbohydrate synthesis are still limited. Although a range of effective glycosylation approaches have been developed, new glycosylation methods based on novel mechanisms are still urgently needed which can rapidly and stereoselectively assemble glycosidic linkages that prove challenging with existing technologies. Our long-term goal is to develop new stereoselective glycosylation technologies that address challenging glycosidic linkages based on novel mechanisms. The objective of the proposed research is to develop a series of iron-catalyzed one-step glycal cis-amidoglycosylation approaches to assemble a wide variety of 1,2-cis-amido glycosidic linkages that prove challenging with existing methods. Our underlying idea of this exploratory research is that a structurally unique iron-nitrenoid may bypass the conventional oxocarbenium ion-based glycosylation pathways, and that it can stereoselectively transfer both an amido group and an iron-bound glycosyl acceptor in nearly exclusive cis-fashion to a glycal, presumably through a 2- amidoglycosyl radical species. The proposed research will explore this idea in the context of two Specific Aims. First, we plan to discover new iron catalysts and amination reagents and develop a range of iron-catalyzed cis- amidoglycosylation approaches that effectively assemble a variety of cis-amido glycosidic linkages. Second, we will further develop this new approach into robust technology for complex-carbohydrate synthesis. This proposed approach is innovative because it explores the new glycosylation approaches in a context that significantly departs both from the well-known oxocarbenium ion-based glycosylation strategies and from the established reactivity of metal-nitrenoids. The proposed research is significant because it will provide a general solution to assemble 1,2-cis-amido glycosidic linkages and lay the foundation for the development of an array of under-explored, earth-abundant metal-catalyzed approaches for challenging glycosidic-bond formation. Completion of the proposed research will provide a range of iron-catalyzed methods that effectively afford a wide variety of 1,2-cis-amido glycosidic linkages. These robust and easily adaptable synthetic approaches will complement the known methods and fill an important gap of existing glycosylation technologies. Further development of this technology will add valuable tools for the automated carbohydrate synthesis, which will significantly advance biomedical sciences.